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Kowshik J.,Annamalai University | Baba A.B.,Annamalai University | Giri H.,Indian Institute of Technology Madras | Reddy G.D.,Medicinal Chemistry Research Division | And 2 more authors.
PLoS ONE | Year: 2014

Identifying agents that inhibit STAT-3, a cytosolic transcription factor involved in the activation of various genes implicated in tumour progression is a promising strategy for cancer chemoprevention. In the present study, we investigated the effect of dietary astaxanthin on JAK-2/STAT-3 signaling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model by examining the mRNA and protein expression of JAK/STAT-3 and its target genes. Quantitative RT-PCR, immunoblotting and immunohistochemical analyses revealed that astaxanthin supplementation inhibits key events in JAK/STAT signaling especially STAT-3 phosphorylation and subsequent nuclear translocation of STAT- 3. Furthermore, astaxanthin downregulated the expression of STAT-3 target genes involved in cell proliferation, invasion and angiogenesis, and reduced microvascular density, thereby preventing tumour progression. Molecular docking analysis confirmed inhibitory effects of astaxanthin on STAT signaling and angiogenesis. Cell culture experiments with the endothelial cell line ECV304 substantiated the role of astaxanthin in suppressing angiogenesis. Taken together, our data provide substantial evidence that dietary astaxanthin prevents the development and progression of HBP carcinomas through the inhibition of JAK-2/STAT-3 signaling and its downstream events. Thus, astaxanthin that functions as a potent inhibitor of tumour development and progression by targeting JAK/STAT signaling may be an ideal candidate for cancer chemoprevention. © 2014 Kowshik et al. Source


Kusuma P.K.,Medicinal Chemistry Research Division | Vedula G.,Andhra University
Rasayan Journal of Chemistry | Year: 2015

In present research; we tried to confirm 2-phenyl Quinazolin-4(3H)-one derivatives, which are broadly reported in the literature as scavenging agent. The study was carried out on a selected set of 40 novel 2-phenyl quinazoline- 4(3H)-one and consequently docked them into Scavenger receptor class B Type- I (SRCB 1). The analogues 7a-7a8 and 7b1-7b8 were found to be more potent inhibitor as they exhibit drug like activity. The entire test Compounds which have highest ligand energy compared to the Standard compounds. Structure based drug designing of these analogues may found a novel antioxidant for future study. © 2015, Rasayan Journal of Chemistry, c/o Dr. Pratima Sharma. All rights reserved. Source


Karuppasamy M.,Birla Institute of Technology | Mahapatra M.,Birla Institute of Technology | Yabanoglu S.,Hacettepe University | Ucar G.,Hacettepe University | And 6 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

3,5-Diaryl pyrazolines analogs were synthesized and evaluated for their monoamine oxidase (MAO) inhibitory activity. The compounds were found reversible and selective towards MAO-A with selectivity index in the magnitude of 103-105. The docking studies were carried out to gain further structural insights of the binding mode and possible interactions with the active site of MAO-A. Interestingly, the theoretical (Ki) values obtained by molecular docking studies were in congruence with their experimental (Ki) values. © 2010 Elsevier Ltd. All rights reserved. Source


Sirisha K.,Kakatiya University | Shekhar M.C.,Indian National Institute of Pharmaceutical Education and Research | Umasankar K.,Medicinal Chemistry Research Division | Mahendar P.,Kakatiya University | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2011

The overexpression of multidrug resistance protein 1 (MRP1) by tumor cells results in multidrug resistance (MDR) to structurally unrelated anticancer drugs. Circumvention of MDR by combination of chemosensitizers with antitumor compounds is a new field of investigation in cancer chemotherapy. Much effort has been put-in recently to identify the modulators/inhibitors of MRP1 to overcome the MDR. 1,4-Dihydropyridine (DHP) derivatives are indicated to be a new class of MRP1 inhibitors in cancer treatment. Molecular docking studies were carried out on 48 newly synthesized DHP derivatives with the crystal structure of MRP1 to gain some structural insights on the binding mode and possible interactions with the active site of MRP1 (NBD1). The 10 top-ranked molecules were selectively evaluated, experimentally for their MRP1 inhibitory effect using the insect cell membrane MRP1 ATPase assay. The inhibitory capacity (IC50 concentrations) of the test compounds was compared with the reported IC50- or the Ki-concentrations for benzbromarone, a standard MRP1 inhibitor. Amongst the compounds tested, compounds IA 1 and IIA5 were found to exhibit a potent MRP1 inhibitory action with IC50 values of 20 ± 4 and 14 ± 2 μM (mean ± SD), respectively as compared to benzbromarone (IC50 = 4 μM). The compound IIA5, in particular was found to be more potent than IA1 in accordance with the docking results. These new DHP derivatives possess promising characteristics for their development as MDR reversal agents. © 2011 Elsevier Ltd. All rights reserved. Source


Tippani R.,Kakatiya University | Porika M.,Kakatiya University | Sirisha K.,Medicinal Chemistry Research Division | Abbagani S.,Kakatiya University | Thammidala C.,Kakatiya University
Current Pharmaceutical Biotechnology | Year: 2014

Pterostilbene is a naturally occurring dimethyl ether analog of resveratrol identified in several plant species. Telomerase is important in tumor initiation and cellular immortalization. Given the striking correlations between telomerase activity and proliferation capacity in tumor cells, telomerase had been considered as a potentially important molecular target in cancer therapeutics. Molecular docking studies were performed on pterostilbene with the crystal structure of telomerase (3DU6). Pterostilbene was evaluated for its in vitro cytotoxicity in breast (MCF7) and lung cancer (NCI H-460) cell lines, antimitotic activity in green grams and telomerase activity. Curcumin was used as a standard. Docking results indicated good interaction between pterostilbene and the active site of telomerase and the docked energy of pterostilbene was -7.10 kcal/mol. Pterostilbene showed strong inhibitory effect on in vitro telomerase activity and cell growth in both the cell lines tested in a dose dependent manner. Cancer cells treated with 80 μM pterostilbene exhibited significant telomerase inhibition, after 72 hours (MCF-7 and NCI H-460; 81.52% and 74.69% reduction, respectively, compared to control). The IC50 of pterostilbene for anti-proliferative activity in MCF7 and NCI H-460 cell lines were found to be 30.0 and 47.2 μM, respectively. The best antimitotic activity was obtained with 80 μM of pterostilbene (100% reduction in water imbibition). All the above results were comparable to that of curcumin. The drug-related properties of pterostilbene were calculated using Molinspiration, Osiris Property Explorer and ACD/Chemsketch softwares. Pterostilbene obeyed Lipinski's Rule of Five indicating its therapeutic potential in humans. It was found that the telomerase inhibitory activity exhibited by pterostilbene was dependent of the cell viability and has the potential to be a new drug candidate against breast and lung cancers. © 2013 Bentham Science Publishers. Source

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